Bisphosphonates adverse-events meta-analysis results

Overview

This report describes the meta-analysis of aggregate data on adverse effects of bisphosphonates.

26 studies are considered, which in total reported 112 distinctly-named adverse events. Among these events, there are 102 distinct events for which there is at least one study comparing incidence of that event between a bisphosphonate treatment group and a no-bisphosphonate control group.

For each of these 102 events, the data were analysed in the same way. The methods, and highlighted results, are given in in this document. Extra details for each of these analyses are reported in Appendix 2.

Events might be grouped into categories corresponding to similar physiological systems (as advised by a clinician REF). Here they are analysed independently, though the results are presented in groups.

Treatment groupings

For each event, there is a different set of trials that reported data on that event, giving a different network of comparisons between treatments. Five alternative models for network meta-analysis are compared, defined by different groupings of treatments. From the finest to the coarsest grouping, these are:

1. Different doses and delivery methods of different drugs considered as different treatments. The network corresponding to this model is shown as the “full network of comparisons” in Appendix 2.

2. Different delivery methods considered as different treatments, but different doses of the same drug considered as the same treatment.

3. Different drugs considered as different treatments, but different doses and delivery methods of the same drug considered as the same treatment.

4. Nitrogenous bisphosphonates and non-nitrogenous bisphosphonates (just clodronate) considered as different treatments.

5. All bisphosphonates considered as the same treatment.

Non-bisphosphonate control groups were distinguished as either placebo, observation-only or denosumab.

In two studies, treatment arms are distinguished by the different hormone therapies given. These are modelled in the same way as different doses of the same drug. (In Appendix 2, the arm given a hormone therapy that is not an aromatase inhibitor is labelled “notai”).

Network meta-analysis procedure

A network meta-analysis model was obtained for each event using the following procedure. This procedure aims to find the best-fitting model which uses all potentially-relevant data, which requires a “connected network” of treatments.

1. If the treatment network is disconnected under the finest model (grouping 1), but becomes connected when placebo and observation-only controls are considered to be the same treatment, then these two control groups are considered to be the same. Otherwise these controls are separated.

2. Starting with the finest model (grouping 1), the treatments are grouped until the resulting treatment network is connected.

3. All network meta-analysis models ranging from the finest connected model to the coarsest are fitted.

4. The optimal model is selected from among those which fitted successfully, using the deviance information criterion (DIC REF), a measure of model fit or predictive ability. The network diagram for the selected model is shown in Appendix 2.

5. If no network meta-analysis model fitted successfully, then the results for that event are reported from direct-data meta-analysis only. Unsuccessful fits are generally due to sparsity of information.

Technical details of the network meta-analysis models, and the model comparison and checking procedure, are reported in Appendix 1.

For the selected model, a corresponding classical meta-analysis is also performed based on the direct comparisons alone.

Full network graph

## Warning in GGally::ggnet2(g, label = labels, edge.label = edge.label, edge.size = E(g)$weight, : ggnet2 does not know how to handle self-loops

Results

Table 1: events affected most by bisphosphonate treatment

This table lists the events and treatments for which either the direct comparison or the selected network meta-analysis model produced a practically and statistically significant treatment effect, defined as either

• an odds ratio with a posterior median of 1.5 or greater, or
• a risk difference (for either healthy or cancer patients) with a posterior median of 0.02 or greater,

which is also “statistically significant” (lower credible limit greater than 1 for odds ratios, or 0 for risk differences).

The odds ratio is the ratio of the odds of the event between the treatment group (as defined in the table) and an “observation only” control group.

The risk difference is the estimated absolute risk for patients given the active treatment, minus a constant baseline risk. These baseline risks are listed in the table below. For cancer patients they are obtained from classical meta-analysis of the direct data from the “observation-only” arms of the bisphosphonate trials. For “healthy” patients they are obtained from the placebo arm of the NCT00083174 study of exemestane v placebo for postmenopausal women at high risk of breast cancer. The risk differences are (currently) only calculated under the network meta-analysis model.

Where there is no baseline risk / risk difference for healthy women, this is because the event was not reported in the NCT00083174 study. If the baseline risk is close to zero, then the risk difference will also be negligible.

		Treatment	Direct OR	NMA OR	Baseline risk (cancer)	Risk difference (cancer)	Baseline risk (healthy)	Risk difference (healthy)	Proportion of graded events that are serious
MYALGIA
	MYALGIA	Ibandronate		2.04 (1.13, 3.85)	0.03	0.03 (0, 0.09)			0.06 (39/611)
	MYALGIA	Pamidronate		2.32 (1.09, 5.21)	0.03	0.04 (0, 0.12)			(0/0)
	MYALGIA	Zoledronic_acid	1.52 (1.31, 1.75)	2.36 (1.61, 3.6)	0.03	0.04 (0.02, 0.08)			0.03 (47/1343)
	stiffness	Zoledronic_acid_2_IV	2.72 (1.46, 5.06)	2.76 (1.27, 5.83)	0.02	0.03 (0, 0.07)			0 (0/37)
OTHERS
	ABDOMINAL PAIN	Bisphosphonate	1.51 (1.13, 2.02)	1.51 (1.1, 2.11)	0.13	0.05 (0.01, 0.11)			0.1 (122/1277)
	ARTHRALGIA	Nitrogenous	1.53 (1.29, 1.81)	1.54 (1.28, 1.86)	0.17	0.07 (0.04, 0.1)	0.0000	0 (0, 0)	0.04 (189/5071)
	BACK PAIN	Nitrogenous	1.54 (1, 2.37)	1.64 (1.08, 2.69)	0.08	0.05 (0.01, 0.11)	0.1	0.05 (0.01, 0.13)	0.03 (37/1247)
	CARDIAC EVENTS	Nitrogenous	2.51 (1.52, 4.17)	2.73 (1.33, 6.31)	0.03	0.04 (0.01, 0.12)	0.0020	0 (0, 0.01)	0.62 (143/231)
	CARDIAC EVENTS	Non_nitrogenous	5.22 (0.25, 109.67)	4.35 (1.44, 13.6)	0.03	0.08 (0.01, 0.25)	0.0020	0.01 (0, 0.02)	0.32 (21/65)
	CHILLS	Zoledronic_acid_IV	8.55 (2.26, 32.32)	15.19 (3.96, 94.86)	0.02	0.24 (0.06, 0.66)			0.01 (3/213)
	DIARRHOEA	Non_nitrogenous	3.34 (1.18, 9.45)	1.81 (1.35, 2.74)	0.11	0.07 (0.03, 0.14)	0.03	0.03 (0.01, 0.05)	0.08 (49/591)
	DYSGEUSIA	Zoledronic_acid_2_IV	10.1 (1.17, 87.24)	8.53 (1.25, 119.84)	0.0010	0.01 (0, 0.11)
	FATIGUE	Bisphosphonate	1.13 (1.02, 1.26)	1.28 (1.06, 1.65)	0.1	0.03 (0.01, 0.06)	0.21	0.04 (0.01, 0.09)	0.05 (247/4607)
	FEVER	Pamidronate_IV	1.52 (0.47, 4.92)	4.87 (1.9, 12.62)	0.01	0.05 (0.01, 0.13)			1 (3/3)
	FEVER	Zoledronic_acid_IV	4.06 (3.06, 5.38)	5.2 (2.88, 8.79)	0.01	0.05 (0.02, 0.09)			0.09 (82/933)
	HEADACHE	Zoledronic_acid	1.19 (1.02, 1.4)	1.48 (1.06, 2.25)	0.24	0.08 (0.01, 0.18)			0.03 (36/1304)
	HEPATOTOXICITY	Clodronate_Oral	1.69 (1.05, 2.71)	1.46 (0.78, 2.59)	0.26	0.08 (-0.04, 0.22)			0.15 (14/95)
	HEPATOTOXICITY	Ibandronate_Oral	4.27 (1.28, 14.22)	3.39 (1.13, 11.73)	0.26	0.28 (0.02, 0.54)			(0/0)
	hypertonia/muscle spasms	Bisphosphonate	1.53 (1.02, 2.3)	1.52 (0.93, 2.81)	0.04	0.02 (0, 0.07)			0.14 (15/106)
	HYPOCALCEMIA	Ibandronate		6.15 (1.16, 41.76)	0.04	0.17 (0.01, 0.6)			0.02 (5/210)
	HYPOCALCEMIA	Pamidronate	3.23 (1.45, 7.22)	3.18 (1.2, 8.64)	0.04	0.08 (0.01, 0.23)			(0/0)
	HYPOCALCEMIA	Zoledronic_acid	7.07 (0.87, 57.56)	7.28 (1.36, 48.93)	0.04	0.2 (0.01, 0.64)			0.03 (11/336)
	increased bone pain	Bisphosphonate	1.73 (1.47, 2.04)	1.79 (1.33, 2.49)	0.11	0.07 (0.03, 0.13)			0.1 (352/3386)
	INFECTION	Ibandronate_Oral	2.24 (1.18, 4.22)		0.22		0.0009		(0/0)
	Influenza-like symptoms	Bisphosphonate	22.18 (2.98, 164.89)	16.09 (2.04, 207.85)	0.03	0.33 (0.03, 0.85)			0.05 (35/718)
	NAUSEA	Bisphosphonate	1.21 (1.08, 1.35)	1.33 (1.11, 1.63)	0.34	0.07 (0.02, 0.12)	0.05	0.02 (0.01, 0.03)	0.09 (323/3579)
	NEUROSENSORY PROBLEMS	Bisphosphonate	1.23 (1.05, 1.45)	1.29 (1.05, 1.66)	0.1	0.03 (0, 0.06)	0.0000	0 (0, 0)	0.03 (52/1509)
	OsteoNecrosis of the Jaw	Nitrogenous	7.69 (2.31, 25.55)		0.0050				(0/0)
	periodontal disease	Zoledronic_acid_2_IV	15.34 (0.87, 269.36)	10.2 (1.14, 1322.28)					0.14 (1/7)
	THROMBOEMBOLIC EVENTS	Clodronate		7.27 (1.41, 33.44)	0.02	0.11 (0.01, 0.38)	0.0009	0.01 (0, 0.03)	1 (27/27)
	THROMBOEMBOLIC EVENTS	Ibandronate		13.15 (2.36, 68.93)	0.02	0.19 (0.03, 0.56)	0.0009	0.01 (0, 0.06)	0.91 (10/11)
	THROMBOEMBOLIC EVENTS	Zoledronic_acid	3.18 (1.34, 7.51)	2.79 (0.99, 7.42)	0.02	0.03 (0, 0.11)	0.0009	0 (0, 0.01)	0.72 (28/39)
	VOMITING	Non_nitrogenous		1.67 (1.18, 2.92)	0.19	0.09 (0.03, 0.22)	0.0004	0 (0, 0)	0.03 (9/312)

Note the reported “treatment” in these tables depends on the selected model - this could refer to all bisphosphonates, or the dose and delivery method of a particular drug, or some categorisation in between. If the selected model distinguishes between doses, the dose categories are labelled with a number.

Events that are significant if we just include studies with complete reporting.

The same procedure above was followed to select an optimal network meta-analysis model for the data including just studies with “complete” reporting. About half of the events selected above still have significant treatment effects, though perhaps for a slightly different treatment definition. Many are no longer “significant”, and there are some new ones (hypertonia/muscle spasms, dysgeusia, abdominal pain) that become “significant” by some criterion.

		Treatment	Direct OR	NMA OR	Baseline risk (cancer)	Risk difference (cancer)	Baseline risk (healthy)	Risk difference (healthy)	Proportion of events that are serious
MYALGIA
	MYALGIA	Zoledronic_acid	3.3 (2.06, 5.28)	3.22 (1.65, 5.83)	0.03	0.07 (0.02, 0.14)			0.03 (28/1034)
OTHERS
	BACK PAIN	Nitrogenous	2.19 (0.78, 6.13)	2.46 (1, 6.6)	0.08	0.1 (0, 0.29)	0.1	0.11 (0, 0.32)	0.03 (37/1243)
	CARDIAC EVENTS	Clodronate_1_Oral	5.22 (0.25, 109.67)	7.84 (1.27, 33.46)	0.03	0.15 (0.01, 0.45)	0.0020	0.01 (0, 0.05)	0.32 (21/65)
	CARDIAC EVENTS	Ibandronate_3_Oral		12.18 (2.01, 59.73)	0.03	0.22 (0.03, 0.6)	0.0020	0.02 (0, 0.09)	1 (18/18)
	DIARRHOEA	Non_nitrogenous	3.34 (1.18, 9.45)	2.91 (1.48, 5.94)	0.11	0.15 (0.04, 0.31)	0.03	0.06 (0.02, 0.14)	0.08 (42/503)
	DYSGEUSIA	Bisphosphonate	7.04 (1.2, 41.3)	6.26 (0.95, 74.5)	0.0010	0.01 (0, 0.07)
	FATIGUE	Zoledronic_acid_1_IV	1.94 (1.32, 2.84)	1.9 (0.96, 3.94)	0.1	0.08 (0, 0.21)	0.21	0.12 (-0.01, 0.3)	0.01 (19/1335)
	FATIGUE	Zoledronic_acid_2_IV	1.76 (1.14, 2.73)	2.38 (1.22, 5.15)	0.1	0.11 (0.02, 0.27)	0.21	0.18 (0.04, 0.37)	0 (0/362)
	FEVER	Clodronate_1_Oral		6.54 (1.84, 45.74)	0.01	0.06 (0.01, 0.36)			0.01 (1/83)
	FEVER	Ibandronate_3_Oral		8.83 (2.48, 60.44)	0.01	0.09 (0.02, 0.42)			0 (0/70)
	FEVER	Zoledronic_acid_1_IV	17.55 (4.24, 72.7)	27.03 (10.19, 179.58)	0.01	0.25 (0.1, 0.69)			0.05 (28/570)
	FEVER	Zoledronic_acid_2_IV	34.76 (8.48, 142.55)	30.72 (11.84, 178.43)	0.01	0.27 (0.12, 0.68)			0.03 (6/192)
	FEVER	Zoledronic_acid_4_IV		6.8 (2.23, 38.99)	0.01	0.07 (0.02, 0.32)			0.08 (3/37)
	HEADACHE	Zoledronic_acid_IV	2.19 (1.36, 3.52)	2.29 (1.32, 3.93)	0.24	0.18 (0.05, 0.31)			0.02 (22/931)
	hypertonia/muscle spasms	Bisphosphonate	3.68 (1.12, 12.05)	3.57 (0.94, 22.24)	0.04	0.1 (0, 0.46)			0.21 (12/58)
	HYPOCALCEMIA	Bisphosphonate	1.6 (1.03, 2.51)	1.5 (0.76, 2.81)	0.04	0.02 (-0.01, 0.07)			0.02 (9/502)
	increased bone pain	Bisphosphonate	1.84 (1.37, 2.48)	1.86 (1.15, 3.08)	0.11	0.08 (0.02, 0.17)			0.07 (147/2131)
	NEUROSENSORY PROBLEMS	Bisphosphonate	1.56 (1.1, 2.21)	1.49 (1, 2.23)	0.1	0.04 (0, 0.1)	0.0000	0 (0, 0)	0.02 (23/1429)
	NEUTROPENIA	Nitrogenous	2.04 (0.7, 5.93)	2.33 (1, 5.43)	0.04	0.05 (0, 0.15)			0.05 (8/166)
	SKIN DISORDER	Bisphosphonate	1.6 (1.03, 2.48)	1.48 (0.87, 2.44)	0.05	0.02 (-0.01, 0.06)			0.03 (37/1142)
	THROMBOEMBOLIC EVENTS	Ibandronate		33.15 (1.62, 474.44)	0.02	0.38 (0.01, 0.88)	0.0009	0.03 (0, 0.3)	1 (10/10)
	THROMBOEMBOLIC EVENTS	Zoledronic_acid	7.97 (1.4, 45.55)	4.38 (0.53, 46.06)	0.02	0.06 (-0.01, 0.46)	0.0009	0 (0, 0.04)	0.67 (18/27)

Change in results when excluding incomplete reporting

The graph below shows all the events for which

• a significant odds ratio was highlighted in the main analysis.

• no significant odds ratio was detected when studies with incomplete reporting were excluded

The treatment categorisations are shown under the best fitting model in the main analysis. Comparing the red and blue lines shows how the results change when studies with incomplete reporting are excluded.

Table 2: Summary of results for every event

Table 2 gives odds ratios from direct and selected network meta-analysis models for all events, sorted by clinical category, including non-significant results. Effects significant by either criterion, as listed in Table 1, are shown here in red.

More detailed results, for all 103 events, including network diagrams, raw data and “forest plots” of meta-analysis results, are given in Appendix 2.

		Treatment	Direct OR	NMA OR	Baseline risk (cancer)	Risk difference (cancer)	Baseline risk (healthy)	Risk difference (healthy)
MYALGIA
	MYALGIA	Clodronate		1.24 (0.59, 2.6)	0.03	0.01 (-0.01, 0.05)
	MYALGIA	Ibandronate		2.04 (1.13, 3.85)	0.03	0.03 (0, 0.09)
	MYALGIA	Pamidronate		2.32 (1.09, 5.21)	0.03	0.04 (0, 0.12)
	MYALGIA	Zoledronic_acid	1.52 (1.31, 1.75)	2.36 (1.61, 3.6)	0.03	0.04 (0.02, 0.08)
	stiffness	Zoledronic_acid_2_IV	2.72 (1.46, 5.06)	2.76 (1.27, 5.83)	0.02	0.03 (0, 0.07)
	stiffness	Zoledronic_acid_2notai_IV	1.28 (0.58, 2.85)	1.2 (0.47, 3.09)	0.02	0 (-0.01, 0.03)
OTHERS
	ABDOMINAL PAIN	Bisphosphonate	1.51 (1.13, 2.02)	1.51 (1.1, 2.11)	0.13	0.05 (0.01, 0.11)
	ALANINE AMINOTRANSFERASE	Clodronate_1_Oral		0.15 (0.02, 3.1)	0.0090	-0.01 (-0.01, 0.02)	0.0004	0 (0, 0)
	ALANINE AMINOTRANSFERASE	Ibandronate_3_Oral		0.05 (0.01, 1.15)	0.0090	-0.01 (-0.01, 0)	0.0004	0 (0, 0)
	ALANINE AMINOTRANSFERASE	Ibandronate_4_IVAndOral		0.05 (0, 2.34)	0.0090	-0.01 (-0.01, 0.01)	0.0004	0 (0, 0)
	ALANINE AMINOTRANSFERASE	Zoledronic_acid_1_IV	0.34 (0.01, 8.33)	0.07 (0.01, 1.38)	0.0090	-0.01 (-0.01, 0)	0.0004	0 (0, 0)
	ALANINE AMINOTRANSFERASE	Zoledronic_acid_2_IV		0.08 (0.01, 1.98)	0.0090	-0.01 (-0.01, 0.01)	0.0004	0 (0, 0)
	ALKALINE PHOSPHATASE	Zoledronic_acid_1_IV	0.45 (0.09, 2.22)		0.15		0.0000
	ALKALINE PHOSPHATASE	Zoledronic_acid_2_IV	0.26 (0.05, 1.33)		0.15		0.0000
	ALLERGIC REACTIONS	Zoledronic_acid	3.27 (0.13, 83.03)	0.29 (0.01, 24.71)			0.0000	0 (0, 0)
	ALOPECIA	Bisphosphonate	1.05 (0.92, 1.21)	1.11 (0.87, 1.55)	0.06	0.01 (-0.01, 0.03)
	ANAEMIA	Nitrogenous	1.16 (0.5, 2.68)	1.13 (0.61, 2.17)	0.01	0 (0, 0.01)
	ANAEMIA	Non_nitrogenous	1.01 (0.43, 2.39)	0.96 (0.5, 1.82)	0.01	0 (-0.01, 0.01)
	ARTHRALGIA	Nitrogenous	1.53 (1.29, 1.81)	1.54 (1.28, 1.86)	0.17	0.07 (0.04, 0.1)	0.0000	0 (0, 0)
	ARTHRALGIA	Non_nitrogenous		1.2 (0.93, 1.58)	0.17	0.03 (-0.01, 0.07)	0.0000	0 (0, 0)
	arthropathy/arthritis	Bisphosphonate	1.23 (0.88, 1.72)	1.17 (0.79, 1.69)	0.11	0.02 (-0.02, 0.06)	0.09	0.01 (-0.02, 0.05)
	ASPARTATE AMINOTRANSFERASE	Nitrogenous	0.32 (0.1, 1.01)	0.52 (0.2, 1.44)	0.02	-0.01 (-0.01, 0.01)	0.0004	0 (0, 0)
	ASPARTATE AMINOTRANSFERASE	Non_nitrogenous	1.44 (0.55, 3.8)	1.2 (0.42, 3.18)	0.02	0 (-0.01, 0.04)	0.0004	0 (0, 0)
	ASTHENIA	Nitrogenous	2.53 (0.49, 13.13)	2 (0.43, 8.3)	0.08	0.07 (-0.04, 0.33)
	BACK PAIN	Nitrogenous	1.54 (1, 2.37)	1.64 (1.08, 2.69)	0.08	0.05 (0.01, 0.11)	0.1	0.05 (0.01, 0.13)
	BACK PAIN	Non_nitrogenous		1.31 (0.79, 2.36)	0.08	0.02 (-0.02, 0.09)	0.1	0.03 (-0.02, 0.11)
	BILIRUBIN	Bisphosphonate	0.15 (0.03, 0.83)	0.07 (0.01, 0.58)	0.08	-0.07 (-0.08, -0.03)
	CARDIAC: CONGESTIVE HEART FAILURE	Zoledronic_acid_IV	0.2 (0.01, 5.17)	0.05 (0.01, 1.71)	0.04	-0.03 (-0.04, 0.02)
	CARDIAC EVENTS	Nitrogenous	2.51 (1.52, 4.17)	2.73 (1.33, 6.31)	0.03	0.04 (0.01, 0.12)	0.0020	0 (0, 0.01)
	CARDIAC EVENTS	Non_nitrogenous	5.22 (0.25, 109.67)	4.35 (1.44, 13.6)	0.03	0.08 (0.01, 0.25)	0.0020	0.01 (0, 0.02)
	CATARACT	Bisphosphonate	0.84 (0.26, 2.75)	0.44 (0.03, 1.8)	0.0040	0 (0, 0)
	CELLULITIS	Bisphosphonate	0.21 (0.01, 5.28)	0.02 (0, 0.64)	0.04	-0.04 (-0.04, -0.01)
	CHEST PAIN	Bisphosphonate	4.71 (0.22, 101.87)	0.56 (0.04, 12.08)	0.01	-0.01 (-0.01, 0.12)
	CHILLS	Clodronate_Oral		3.45 (0.73, 25.67)	0.02	0.05 (-0.01, 0.35)
	CHILLS	Ibandronate_Oral		3.28 (0.72, 24.2)	0.02	0.05 (-0.01, 0.33)
	CHILLS	Zoledronic_acid_IV	8.55 (2.26, 32.32)	15.19 (3.96, 94.86)	0.02	0.24 (0.06, 0.66)
	COLITIS	Nitrogenous		0.02 (0, 1)	0.0006	0 (0, 0)	0.0004	0 (0, 0)
	COLITIS	Non_nitrogenous	1.01 (0.06, 16.11)	0.4 (0.01, 5.82)	0.0006	0 (0, 0)	0.0004	0 (0, 0)
	constipation	Bisphosphonate	1.06 (0.93, 1.21)	1.03 (0.82, 1.26)	0.42	0.01 (-0.05, 0.06)
	COUGH	Bisphosphonate	1.99 (0.96, 4.13)	1.81 (0.96, 3.63)	0.02	0.01 (0, 0.04)	0.12	0.08 (0, 0.21)
	CPK increased	Clodronate_1_Oral	5.04 (0.24, 105.07)	5.48 (0.05, 3472.85)	0.0003	0 (0, 0.52)
	DECREASED APPETITE	Nitrogenous	0.98 (0.58, 1.67)	0.89 (0.45, 1.92)	0.04	0 (-0.02, 0.03)
	DEHYDRATION	Bisphosphonate	1.18 (0.44, 3.15)	0.91 (0.26, 3.27)	0.0080	0 (-0.01, 0.02)
	DEPRESSION	Bisphosphonate	0.96 (0.76, 1.2)	0.96 (0.72, 1.32)	0.02	0 (0, 0.01)	0.1	0 (-0.03, 0.03)
	DIARRHOEA	Nitrogenous	0.99 (0.84, 1.16)	1.1 (0.88, 1.55)	0.11	0.01 (-0.01, 0.05)	0.03	0 (0, 0.02)
	DIARRHOEA	Non_nitrogenous	3.34 (1.18, 9.45)	1.81 (1.35, 2.74)	0.11	0.07 (0.03, 0.14)	0.03	0.03 (0.01, 0.05)
	DIZZINESS	Bisphosphonate	1.44 (0.89, 2.32)	1.33 (0.74, 2.4)	0.03	0.01 (-0.01, 0.04)	0.09	0.03 (-0.02, 0.1)
	dry mouth	Bisphosphonate	0.55 (0.2, 1.52)	0.4 (0.12, 1.16)	0.04	-0.02 (-0.04, 0.01)
	DYSGEUSIA	Clodronate_1_Oral	3.02 (0.12, 74.25)	1.53 (0.02, 566.04)	0.0010	0 (0, 0.37)
	DYSGEUSIA	Ibandronate_3_Oral		1.06 (0.35, 4.52)	0.0010	0 (0, 0)
	DYSGEUSIA	Zoledronic_acid_1_IV	1.07 (0.85, 1.35)	1.09 (0.46, 2.86)	0.0010	0 (0, 0)
	DYSGEUSIA	Zoledronic_acid_2_IV	10.1 (1.17, 87.24)	8.53 (1.25, 119.84)	0.0010	0.01 (0, 0.11)
	DYSPEPSIA	Clodronate		0.44 (0.06, 3.28)	0.04	-0.02 (-0.04, 0.08)
	DYSPEPSIA	Ibandronate		0.47 (0.06, 3.59)	0.04	-0.02 (-0.04, 0.09)
	DYSPEPSIA	Risedronate		0.29 (0.03, 2.72)	0.04	-0.03 (-0.04, 0.06)
	DYSPEPSIA	Zoledronic_acid	0.48 (0.04, 5.46)	0.2 (0.03, 1.51)	0.04	-0.03 (-0.04, 0.02)
	dysphagia	Bisphosphonate	0.5 (0.11, 2.3)	0.28 (0.04, 2.64)	0.08	-0.05 (-0.07, 0.1)	0.0000	0 (0, 0)
	DYSPNOEA	Nitrogenous	1.47 (0.7, 3.11)	1.34 (0.58, 3.19)	0.02	0.01 (-0.01, 0.04)	0.0004	0 (0, 0)
	DYSPNOEA	Non_nitrogenous		0.94 (0.38, 2.33)	0.02	0 (-0.01, 0.03)	0.0004	0 (0, 0)
	Elevated creatinine	Clodronate_Oral		1.24 (0.18, 6.04)	0.08	0.02 (-0.07, 0.27)
	Elevated creatinine	Ibandronate_IV		0.86 (0.05, 9.43)	0.08	-0.01 (-0.08, 0.38)
	Elevated creatinine	Ibandronate_Oral		0.78 (0.07, 4.88)	0.08	-0.02 (-0.08, 0.23)
	Elevated creatinine	Pamidronate_IV	0.93 (0.33, 2.64)	0.64 (0.13, 2.39)	0.08	-0.03 (-0.07, 0.1)
	Elevated creatinine	Zoledronic_acid_IV	1.15 (0.16, 8.36)	0.74 (0.09, 2.63)	0.08	-0.02 (-0.08, 0.11)
	endometrial hyperplasia	Zoledronic_acid_IV	1.12 (0.74, 1.72)
	FATIGUE	Bisphosphonate	1.13 (1.02, 1.26)	1.28 (1.06, 1.65)	0.1	0.03 (0.01, 0.06)	0.21	0.04 (0.01, 0.09)
	FEBRILE NEUTROPENIA	Clodronate		1.07 (0.05, 8.39)	0.0040	0 (0, 0.03)
	FEBRILE NEUTROPENIA	Ibandronate		4.56 (0.36, 39.36)	0.0040	0.02 (0, 0.14)
	FEBRILE NEUTROPENIA	Zoledronic_acid	0.98 (0.79, 1.23)	0.85 (0.18, 1.28)	0.0040	0 (0, 0)
	FEVER	Clodronate_Oral		0.64 (0.16, 2.36)	0.01	0 (-0.01, 0.02)
	FEVER	Ibandronate_IV		2.56 (0.44, 13.76)	0.01	0.02 (-0.01, 0.14)
	FEVER	Ibandronate_Oral		0.49 (0.09, 2.03)	0.01	-0.01 (-0.01, 0.01)
	FEVER	Pamidronate_IV	1.52 (0.47, 4.92)	4.87 (1.9, 12.62)	0.01	0.05 (0.01, 0.13)
	FEVER	Zoledronic_acid_IV	4.06 (3.06, 5.38)	5.2 (2.88, 8.79)	0.01	0.05 (0.02, 0.09)
	GGT increased	Non_nitrogenous	5.04 (0.24, 105.07)	4.89 (0.14, 9458.49)	0.0003	0 (0, 0.74)
	HAND-FOOT SYNDROME	Clodronate_1_Oral	3.02 (0.12, 74.25)		0.0080
	HAND-FOOT SYNDROME	Zoledronic_acid_1_IV	0.91 (0.05, 17.05)		0.0080
	HAND-FOOT SYNDROME	Zoledronic_acid_2_IV	2.08 (0.12, 36.73)		0.0080
	HEADACHE	Clodronate		0.96 (0.45, 1.78)	0.24	-0.01 (-0.12, 0.12)
	HEADACHE	Ibandronate		1.08 (0.59, 1.86)	0.24	0.01 (-0.08, 0.13)
	HEADACHE	Pamidronate		1.77 (0.86, 4.09)	0.24	0.12 (-0.03, 0.32)
	HEADACHE	Risedronate		0.91 (0.3, 2.76)	0.24	-0.02 (-0.15, 0.23)
	HEADACHE	Zoledronic_acid	1.19 (1.02, 1.4)	1.48 (1.06, 2.25)	0.24	0.08 (0.01, 0.18)
	HEPATOTOXICITY	Clodronate_Oral	1.69 (1.05, 2.71)	1.46 (0.78, 2.59)	0.26	0.08 (-0.04, 0.22)
	HEPATOTOXICITY	Ibandronate_Oral	4.27 (1.28, 14.22)	3.39 (1.13, 11.73)	0.26	0.28 (0.02, 0.54)
	HEPATOTOXICITY	Zoledronic_acid_IV	1.08 (0.6, 1.95)	1.2 (0.65, 2.28)	0.26	0.04 (-0.07, 0.19)
	HOT FLUSHES	Bisphosphonate	0.95 (0.82, 1.1)	0.93 (0.78, 1.1)	0.24	-0.01 (-0.04, 0.02)	0.32	-0.02 (-0.05, 0.02)
	HYPERGLYCAEMIA	Clodronate_1_Oral	0.62 (0.26, 1.49)	0.61 (0.18, 1.7)	0.0100	0 (-0.01, 0.01)
	HYPERGLYCAEMIA	Ibandronate_3_Oral		0.55 (0.1, 1.79)	0.0100	0 (-0.01, 0.01)
	HYPERGLYCAEMIA	Zoledronic_acid_1_IV		0.68 (0.11, 2.11)	0.0100	0 (-0.01, 0.01)
	HYPERGLYCAEMIA	Zoledronic_acid_2_IV	2.55 (0.99, 6.61)	2.51 (0.68, 9.11)	0.0100	0.01 (0, 0.07)
	HYPERTENSION	Nitrogenous	1.04 (0.36, 3.04)	0.97 (0.38, 2.59)	0.02	0 (-0.01, 0.03)	0.16	0 (-0.09, 0.17)
	HYPERTENSION	Non_nitrogenous		1.31 (0.49, 3.61)	0.02	0.01 (-0.01, 0.04)	0.16	0.04 (-0.07, 0.25)
	hypertonia/muscle spasms	Bisphosphonate	1.53 (1.02, 2.3)	1.52 (0.93, 2.81)	0.04	0.02 (0, 0.07)
	hypoalbuminemia	Bisphosphonate	5.04 (0.24, 105.07)	3.28 (0.05, 301.58)	0.0003	0 (0, 0.08)
	HYPOCALCEMIA	Clodronate		5.56 (0.94, 37.94)	0.04	0.15 (0, 0.58)
	HYPOCALCEMIA	Ibandronate		6.15 (1.16, 41.76)	0.04	0.17 (0.01, 0.6)
	HYPOCALCEMIA	Pamidronate	3.23 (1.45, 7.22)	3.18 (1.2, 8.64)	0.04	0.08 (0.01, 0.23)
	HYPOCALCEMIA	Zoledronic_acid	7.07 (0.87, 57.56)	7.28 (1.36, 48.93)	0.04	0.2 (0.01, 0.64)
	HYPOKALAEMIA	Clodronate_1_Oral	2.36 (0.61, 9.12)		0.01
	HYPOKALAEMIA	Zoledronic_acid_1_IV	1.35 (0.17, 10.92)		0.01
	HYPOKALAEMIA	Zoledronic_acid_2_IV	0.91 (0.24, 3.43)		0.01
	hyponatremia	Bisphosphonate	7.06 (0.36, 136.81)	2.94 (0.33, 3309.12)	0.0003	0 (0, 0.5)
	Hypophosphatemia	Clodronate	0.34 (0.01, 8.24)	0.04 (0, 0.85)	0.0006	0 (0, 0)
	Hypophosphatemia	Ibandronate		0.06 (0, 1.49)	0.0006	0 (0, 0)
	Hypophosphatemia	Zoledronic_acid		0.07 (0, 1.58)	0.0006	0 (0, 0)
	increased bone pain	Bisphosphonate	1.73 (1.47, 2.04)	1.79 (1.33, 2.49)	0.11	0.07 (0.03, 0.13)
	INFECTION	Clodronate_Oral	1.13 (0.48, 2.66)		0.22		0.0009
	INFECTION	Ibandronate_Oral	2.24 (1.18, 4.22)		0.22		0.0009
	INFECTION	Zoledronic_acid_IV	1.02 (0.88, 1.19)		0.22		0.0009
	Influenza-like symptoms	Bisphosphonate	22.18 (2.98, 164.89)	16.09 (2.04, 207.85)	0.03	0.33 (0.03, 0.85)
	INR increased	Clodronate_1_Oral	0.09 (0.01, 1.65)		0.0030
	INSOMNIA	Bisphosphonate	1.33 (0.59, 2.98)	1.26 (0.64, 2.81)	0.05	0.01 (-0.02, 0.07)	0.08	0.02 (-0.03, 0.12)
	IRREGULAR MENSTRUATION	Bisphosphonate	1.08 (0.5, 2.36)	0.91 (0.31, 2.21)	0.02	0 (-0.02, 0.03)
	ISCHAEMIC CARDIOVASCULAR DISEASE	Zoledronic_acid_IV	5.91 (0.24, 145.97)	3.52 (0.06, 776.16)	0.0030	0.01 (0, 0.72)
	ISCHAEMIC CEREBROVASCULAR EVENT	Bisphosphonate	2.41 (0.68, 8.54)	1.55 (0.43, 6.91)	0.0020	0 (0, 0.01)
	LEUCOCYTOPAENIA	Bisphosphonate	1.11 (0.66, 1.9)	0.99 (0.53, 1.99)	0.7	0 (-0.15, 0.12)
	lipase increased	Non_nitrogenous	9.08 (0.49, 168.86)	12.1 (0.36, 85530.05)	0.0003	0 (0, 0.96)
	LIVER PROBLEMS	Clodronate	0.91 (0.61, 1.37)	0.96 (0.48, 2.27)	0.08	0 (-0.04, 0.08)
	LIVER PROBLEMS	Risedronate	5.2 (0.24, 113.59)	2.86 (0.19, 157.6)	0.08	0.12 (-0.06, 0.85)
	LIVER PROBLEMS	Zoledronic_acid	0.15 (0.03, 0.83)	0.07 (0.01, 0.58)	0.08	-0.07 (-0.08, -0.03)
	LOSS OF APPETITE	Bisphosphonate	1.36 (0.6, 3.11)	1.06 (0.43, 2.76)	0.0030	0 (0, 0.01)
	LYMPHOEDEMA	Zoledronic_acid	0.97 (0.13, 7.27)	0.75 (0.16, 3.88)	0.27	-0.05 (-0.21, 0.32)
	LYMPHOPAENIA	Bisphosphonate	0.49 (0.15, 1.66)	0.32 (0.05, 1.19)	0.01	-0.01 (-0.01, 0)
	menometrorrhagia	Zoledronic_acid	2.51 (0.49, 12.97)	2.22 (0.24, 21.14)
	MOTOR NEUROPATHY	Zoledronic_acid_2_IV	1.1 (0.68, 1.79)		0.18
	MUCOSITIS	Bisphosphonate	0.76 (0.26, 2.25)	0.47 (0.09, 1.6)	0.03	-0.01 (-0.03, 0.02)
	MUSCULOSKELETAL PAIN/EVENT	Bisphosphonate	1.33 (1.03, 1.71)	1.35 (0.9, 2.12)	0.11	0.03 (-0.01, 0.1)	0.0004	0 (0, 0)
	Nasopharyngitis	Nitrogenous	0.89 (0.45, 1.75)	0.86 (0.43, 1.79)	0.08	-0.01 (-0.04, 0.05)
	NAUSEA	Bisphosphonate	1.21 (1.08, 1.35)	1.33 (1.11, 1.63)	0.34	0.07 (0.02, 0.12)	0.05	0.02 (0.01, 0.03)
	neuralgia	Nitrogenous	0.15 (0.03, 0.83)	0.23 (0.02, 6.16)	0.02	-0.01 (-0.02, 0.08)
	neuralgia	Non_nitrogenous	4.03 (0.45, 36.14)	1.82 (0.03, 23.05)	0.02	0.01 (-0.02, 0.27)
	NEUROSENSORY PROBLEMS	Bisphosphonate	1.23 (1.05, 1.45)	1.29 (1.05, 1.66)	0.1	0.03 (0, 0.06)	0.0000	0 (0, 0)
	NEUTROPENIA	Bisphosphonate	0.95 (0.79, 1.15)	0.87 (0.49, 1.25)	0.04	0 (-0.02, 0.01)
	neutrophil count decreased	Bisphosphonate	0.67 (0.49, 0.91)	0.6 (0.1, 1.12)	0.07	-0.03 (-0.06, 0.01)
	OEDEMA	Nitrogenous	1.31 (0.87, 1.95)	1.33 (0.88, 2.13)	0.11	0.03 (-0.01, 0.1)
	OEDEMA	Non_nitrogenous		1.14 (0.7, 1.98)	0.11	0.01 (-0.03, 0.08)
	oesophagitis	Clodronate_Oral	5.04 (0.24, 105.07)	1.14 (0.18, 7.15)	0.01	0 (-0.01, 0.07)
	oesophagitis	Ibandronate_Oral	2.46 (0.77, 7.9)	3.29 (0.84, 17.65)	0.01	0.03 (0, 0.17)
	oesophagitis	Zoledronic_acid_IV	0.15 (0.03, 0.83)	0.19 (0.02, 1.28)	0.01	-0.01 (-0.01, 0)
	ORAL MUCOSITIS	Nitrogenous	0.98 (0.85, 1.13)	0.96 (0.59, 1.61)
	OsteoNecrosis of the Jaw	Nitrogenous	7.69 (2.31, 25.55)		0.0050
	OTHER EYE DISORDERS	Clodronate_Oral		1.31 (0.25, 6.33)	0.03	0.01 (-0.03, 0.15)	0.0000	0 (0, 0)
	OTHER EYE DISORDERS	Ibandronate_Oral	0.99 (0.42, 2.34)	0.82 (0.13, 4.71)	0.03	-0.01 (-0.03, 0.11)	0.0000	0 (0, 0)
	OTHER EYE DISORDERS	Pamidronate_IV		0.65 (0.04, 8.83)	0.03	-0.01 (-0.03, 0.21)	0.0000	0 (0, 0)
	OTHER EYE DISORDERS	Risedronate_Oral		0 (0, 0.55)	0.03	-0.03 (-0.03, -0.02)	0.0000	0 (0, 0)
	OTHER EYE DISORDERS	Zoledronic_acid_IV	1.16 (0.85, 1.58)	1 (0.34, 2.46)	0.03	0 (-0.02, 0.05)	0.0000	0 (0, 0)
	pain in extremity	Nitrogenous	2.29 (0.43, 12.16)	1.76 (0.49, 9.82)	0.14	0.08 (-0.07, 0.48)	0.05	0.04 (-0.03, 0.31)
	pain in extremity	Non_nitrogenous		1.56 (0.41, 9.26)	0.14	0.06 (-0.08, 0.46)	0.05	0.03 (-0.03, 0.29)
	PANCREATITIS	Nitrogenous	0.34 (0.01, 8.71)	0.08 (0, 1.25)	0.0006	0 (0, 0)	0.0004	0 (0, 0)
	PANCREATITIS	Non_nitrogenous	5.05 (0.59, 43.24)	1.46 (0.09, 12.17)	0.0006	0 (0, 0.01)	0.0004	0 (0, 0)
	PARAESTHESIA	Nitrogenous	0.82 (0.31, 2.13)	0.57 (0.21, 1.83)	0.43	-0.13 (-0.29, 0.15)
	periodontal disease	Zoledronic_acid_2_IV	15.34 (0.87, 269.36)	10.2 (1.14, 1322.28)
	periodontal disease	Zoledronic_acid_2notai_IV	0.8 (0.21, 2.99)	0.82 (0.14, 4.39)
	phlebitis	Bisphosphonate	1.07 (0.86, 1.33)	1.15 (0.56, 2.56)
	PNEUMONIA	Bisphosphonate	1 (0.39, 2.54)	0.92 (0.21, 3.03)	0.0060	0 (0, 0.01)
	PULMONARY EMBOLUS	Zoledronic_acid_1_IV	1.61 (0.77, 3.38)		0.02
	renal impairment	Bisphosphonate	1.48 (0.7, 3.13)	1.56 (0.7, 3.55)	0.03	0.02 (-0.01, 0.07)	0.0004	0 (0, 0)
	SKIN DISORDER	Bisphosphonate	1 (0.87, 1.14)	1.05 (0.84, 1.4)	0.05	0 (-0.01, 0.02)
	STOMATITIS	Clodronate_1_Oral		1 (0.26, 2.69)	0.15	0 (-0.11, 0.17)
	STOMATITIS	Pamidronate_2_Oral	1.11 (0.85, 1.44)	1.12 (0.71, 1.76)	0.15	0.02 (-0.04, 0.09)
	STOMATITIS	Zoledronic_acid_1_IV	1.05 (0.88, 1.26)	0.99 (0.5, 1.45)	0.15	0 (-0.07, 0.06)
	STOMATITIS	Zoledronic_acid_2_IV		0.33 (0.09, 0.89)	0.15	-0.1 (-0.14, -0.01)
	SYNCOPE	Nitrogenous	3 (0.1, 90.96)	1.11 (0.13, 15.35)	0.0040	0 (0, 0.06)
	SYNCOPE	Non_nitrogenous	1.21 (0.37, 3.97)	0.78 (0.15, 2.97)	0.0040	0 (0, 0.01)
	THROMBOEMBOLIC EVENTS	Clodronate		7.27 (1.41, 33.44)	0.02	0.11 (0.01, 0.38)	0.0009	0.01 (0, 0.03)
	THROMBOEMBOLIC EVENTS	Ibandronate		13.15 (2.36, 68.93)	0.02	0.19 (0.03, 0.56)	0.0009	0.01 (0, 0.06)
	THROMBOEMBOLIC EVENTS	Zoledronic_acid	3.18 (1.34, 7.51)	2.79 (0.99, 7.42)	0.02	0.03 (0, 0.11)	0.0009	0 (0, 0.01)
	THROMBOPAENIA	Bisphosphonate	0.41 (0.06, 2.79)	0.26 (0.03, 1.35)	0.04	-0.03 (-0.04, 0.01)
	THYROID CANCER	Zoledronic_acid	3 (0.1, 90.96)	0.04 (0, 5.68)	0.09	-0.09 (-0.09, 0.27)
	TRAUMATIC FRACTURES	Nitrogenous	0.95 (0.45, 1.99)	0.87 (0.38, 1.95)	0.0060	0 (0, 0.01)
	uterine dilation/curettage	Nitrogenous	1.04 (0.6, 1.82)	0.99 (0.44, 1.95)
	uterine polyp	Zoledronic_acid_2_IV	0.75 (0.26, 2.18)		0.09
	uterine polyp	Zoledronic_acid_2notai_IV	1.15 (0.75, 1.76)		0.09
	VAGINAL BLEEDING	Bisphosphonate	4.03 (0.45, 36.39)	3.31 (0.18, 97.23)	0.0020	0 (0, 0.16)
	VAGINAL DISCHARGE	Bisphosphonate	0.43 (0.11, 1.72)	0.14 (0.02, 0.52)	0.06	-0.06 (-0.06, -0.03)
	VOMITING	Nitrogenous	1.02 (0.89, 1.18)	1.13 (0.89, 1.88)	0.19	0.02 (-0.02, 0.12)	0.0004	0 (0, 0)
	VOMITING	Non_nitrogenous		1.67 (1.18, 2.92)	0.19	0.09 (0.03, 0.22)	0.0004	0 (0, 0)
	MOOD DISTRUBANCES	Nitrogenous	1.24 (0.27, 5.71)	0.88 (0.13, 4.65)

Table 2: Summary of results for every event using only studies with complete reporting

		Treatment	Direct OR	NMA OR	Baseline risk (cancer)	Risk difference (cancer)	Baseline risk (healthy)	Risk difference (healthy)
MYALGIA
	MYALGIA	Clodronate		1.83 (0.69, 3.65)	0.03	0.03 (-0.01, 0.08)
	MYALGIA	Ibandronate		2.55 (0.93, 5.54)	0.03	0.05 (0, 0.13)
	MYALGIA	Zoledronic_acid	3.3 (2.06, 5.28)	3.22 (1.65, 5.83)	0.03	0.07 (0.02, 0.14)
	stiffness	Zoledronic_acid_IV	4.71 (0.22, 101.87)	3.52 (0.19, 1185.28)	0.02	0.04 (-0.01, 0.93)
OTHERS
	ABDOMINAL PAIN	Nitrogenous	2.31 (0.71, 7.55)	2.09 (0.78, 7.33)	0.13	0.11 (-0.03, 0.39)
	ABDOMINAL PAIN	Non_nitrogenous		2.24 (0.77, 8.28)	0.13	0.12 (-0.03, 0.42)
	ALANINE AMINOTRANSFERASE	Nitrogenous	0.53 (0.12, 2.44)	0.76 (0.24, 2.07)	0.0090	0 (-0.01, 0.01)	0.0004	0 (0, 0)
	ALANINE AMINOTRANSFERASE	Non_nitrogenous	2.17 (0.88, 5.33)	1.79 (0.62, 4.69)	0.0090	0.01 (0, 0.03)	0.0004	0 (0, 0)
	ALKALINE PHOSPHATASE	Zoledronic_acid_1_IV	0.45 (0.09, 2.22)		0.15		0.0000
	ALKALINE PHOSPHATASE	Zoledronic_acid_2_IV	0.26 (0.05, 1.33)		0.15		0.0000
	ALOPECIA	Bisphosphonate	1.46 (0.87, 2.43)	1.31 (0.77, 2.27)	0.06	0.02 (-0.01, 0.07)
	ANAEMIA	Bisphosphonate	1.48 (0.74, 2.95)	1.41 (0.67, 2.74)	0.01	0 (0, 0.02)
	ARTHRALGIA	Nitrogenous	1.37 (1, 1.88)	1.34 (0.95, 1.94)	0.17	0.04 (-0.01, 0.11)	0.0000	0 (0, 0)
	ARTHRALGIA	Non_nitrogenous		1.06 (0.71, 1.61)	0.17	0.01 (-0.04, 0.08)	0.0000	0 (0, 0)
	arthropathy/arthritis	Clodronate		1.17 (0.34, 2.91)	0.11	0.02 (-0.07, 0.16)	0.09	0.01 (-0.06, 0.13)
	arthropathy/arthritis	Ibandronate		1.21 (0.24, 3.46)	0.11	0.02 (-0.08, 0.19)	0.09	0.02 (-0.07, 0.16)
	arthropathy/arthritis	Risedronate		0 (0, 0.04)	0.11	-0.11 (-0.11, -0.11)	0.09	-0.09 (-0.09, -0.09)
	arthropathy/arthritis	Zoledronic_acid	1.6 (0.91, 2.81)	1.21 (0.44, 2.38)	0.11	0.02 (-0.06, 0.12)	0.09	0.02 (-0.05, 0.1)
	ASPARTATE AMINOTRANSFERASE	Nitrogenous	0.32 (0.1, 1.01)	0.48 (0.2, 1.37)	0.02	-0.01 (-0.01, 0.01)	0.0004	0 (0, 0)
	ASPARTATE AMINOTRANSFERASE	Non_nitrogenous	1.44 (0.55, 3.8)	1.13 (0.46, 3.07)	0.02	0 (-0.01, 0.04)	0.0004	0 (0, 0)
	ASTHENIA	Risedronate_1_Oral	NA (NA, NA)		0.08
	ASTHENIA	Zoledronic_acid_1_IV	0.84 (0.1, 7)		0.08
	ASTHENIA	Zoledronic_acid_2_IV	0.66 (0.13, 3.35)		0.08
	BACK PAIN	Nitrogenous	2.19 (0.78, 6.13)	2.46 (1, 6.6)	0.08	0.1 (0, 0.29)	0.1	0.11 (0, 0.32)
	BACK PAIN	Non_nitrogenous		1.97 (0.77, 5.58)	0.08	0.07 (-0.02, 0.25)	0.1	0.08 (-0.02, 0.28)
	BILIRUBIN	Bisphosphonate	0.15 (0.03, 0.83)	0.07 (0.01, 0.55)	0.08	-0.07 (-0.08, -0.03)
	CARDIAC: CONGESTIVE HEART FAILURE	Zoledronic_acid	0.2 (0.01, 5.17)	0.06 (0.01, 1.24)	0.04	-0.03 (-0.04, 0.01)
	CARDIAC EVENTS	Clodronate_1_Oral	5.22 (0.25, 109.67)	7.84 (1.27, 33.46)	0.03	0.15 (0.01, 0.45)	0.0020	0.01 (0, 0.05)
	CARDIAC EVENTS	Ibandronate_3_Oral		12.18 (2.01, 59.73)	0.03	0.22 (0.03, 0.6)	0.0020	0.02 (0, 0.09)
	CARDIAC EVENTS	Risedronate_1_Oral		0 (0, 6.6)	0.03	-0.03 (-0.03, 0.13)	0.0020	0 (0, 0.01)
	CARDIAC EVENTS	Zoledronic_acid_1_IV	1.54 (0.63, 3.72)	1.51 (0.56, 3.99)	0.03	0.01 (-0.01, 0.07)	0.0020	0 (0, 0.01)
	CARDIAC EVENTS	Zoledronic_acid_2_IV	3.75 (0.8, 17.66)	2.61 (0.89, 8.17)	0.03	0.04 (0, 0.16)	0.0020	0 (0, 0.01)
	CARDIAC EVENTS	Zoledronic_acid_4_IV		2.49 (0.71, 9.4)	0.03	0.04 (-0.01, 0.18)	0.0020	0 (0, 0.01)
	CATARACT	Bisphosphonate	0.84 (0.26, 2.75)		0.0040
	CELLULITIS	Bisphosphonate	0.21 (0.01, 5.28)	0.02 (0, 0.71)	0.04	-0.04 (-0.04, -0.01)
	CHEST PAIN	Bisphosphonate	4.71 (0.22, 101.87)	0.91 (0.05, 31.56)	0.01	0 (-0.01, 0.27)
	CHILLS	Zoledronic_acid_1_IV	10.35 (0.56, 190.21)		0.02
	CHILLS	Zoledronic_acid_2_IV	8.03 (0.94, 68.6)		0.02
	COLITIS	Bisphosphonate	1.01 (0.06, 16.11)	0.22 (0, 3.07)	0.0006	0 (0, 0)	0.0004	0 (0, 0)
	constipation	Bisphosphonate	0.54 (0.22, 1.3)	0.54 (0.24, 1.38)	0.42	-0.14 (-0.27, 0.08)
	COUGH	Nitrogenous	2.17 (0.47, 10.08)	1.62 (0.42, 6.74)	0.02	0.01 (-0.01, 0.09)	0.12	0.06 (-0.06, 0.36)
	COUGH	Non_nitrogenous		1.51 (0.37, 6.62)	0.02	0.01 (-0.01, 0.08)	0.12	0.05 (-0.07, 0.35)
	CPK increased	Clodronate_Oral	5.04 (0.24, 105.07)	4.95 (0.13, 5537.82)	0.0003	0 (0, 0.63)
	DECREASED APPETITE	Bisphosphonate	4.65 (0.62, 34.85)	5.4 (0.55, 605.12)	0.04	0.13 (-0.02, 0.92)
	DEHYDRATION	Bisphosphonate	1.18 (0.44, 3.15)	0.98 (0.27, 3.15)	0.0080	0 (-0.01, 0.02)
	DEPRESSION	Clodronate_1_Oral		0.89 (0.31, 2.6)	0.02	0 (-0.01, 0.03)	0.1	-0.01 (-0.07, 0.13)
	DEPRESSION	Ibandronate_3_Oral		0.9 (0.31, 2.67)	0.02	0 (-0.01, 0.03)	0.1	-0.01 (-0.07, 0.13)
	DEPRESSION	Zoledronic_acid_1_IV	1.83 (0.44, 7.58)	1.07 (0.42, 3.05)	0.02	0 (-0.01, 0.03)	0.1	0.01 (-0.06, 0.16)
	DEPRESSION	Zoledronic_acid_2_IV	0.86 (0.32, 2.34)	0.93 (0.4, 2.17)	0.02	0 (-0.01, 0.02)	0.1	-0.01 (-0.06, 0.1)
	DEPRESSION	Zoledronic_acid_4_IV		1.38 (0.55, 3.51)	0.02	0.01 (-0.01, 0.04)	0.1	0.03 (-0.04, 0.19)
	DIARRHOEA	Nitrogenous	1.53 (0.66, 3.56)	1.82 (0.96, 3.68)	0.11	0.07 (0, 0.2)	0.03	0.03 (0, 0.08)
	DIARRHOEA	Non_nitrogenous	3.34 (1.18, 9.45)	2.91 (1.48, 5.94)	0.11	0.15 (0.04, 0.31)	0.03	0.06 (0.02, 0.14)
	DIZZINESS	Nitrogenous	1.56 (0.61, 3.95)	1.23 (0.49, 3.39)	0.03	0.01 (-0.01, 0.06)	0.09	0.02 (-0.05, 0.16)
	DIZZINESS	Non_nitrogenous		0.89 (0.26, 2.6)	0.03	0 (-0.02, 0.04)	0.09	-0.01 (-0.07, 0.12)
	dry mouth	Bisphosphonate	0.55 (0.2, 1.52)	0.34 (0.07, 1.11)	0.04	-0.03 (-0.04, 0)
	DYSGEUSIA	Bisphosphonate	7.04 (1.2, 41.3)	6.26 (0.95, 74.5)	0.0010	0.01 (0, 0.07)
	DYSPEPSIA	Clodronate_Oral		0.67 (0.07, 5.45)	0.04	-0.01 (-0.04, 0.15)
	DYSPEPSIA	Ibandronate_Oral		0.85 (0.09, 6.76)	0.04	-0.01 (-0.04, 0.18)
	DYSPEPSIA	Risedronate_Oral		0.43 (0.03, 4.68)	0.04	-0.02 (-0.04, 0.13)
	DYSPEPSIA	Zoledronic_acid_IV	0.48 (0.04, 5.46)	0.26 (0.03, 2.07)	0.04	-0.03 (-0.04, 0.04)
	dysphagia	Bisphosphonate	0.5 (0.11, 2.3)	0.25 (0.05, 2.29)	0.08	-0.06 (-0.07, 0.08)	0.0000	0 (0, 0)
	DYSPNOEA	Zoledronic_acid_2_IV	9.72 (0.51, 186.7)		0.02		0.0004
	Elevated creatinine	Bisphosphonate	1.03 (0.38, 2.78)	1.51 (0.28, 6.52)	0.08	0.04 (-0.06, 0.29)
	FATIGUE	Clodronate_1_Oral		1.16 (0.34, 3.14)	0.1	0.01 (-0.07, 0.16)	0.21	0.03 (-0.12, 0.24)
	FATIGUE	Ibandronate_3_Oral		1.59 (0.48, 5.36)	0.1	0.05 (-0.05, 0.28)	0.21	0.09 (-0.1, 0.38)
	FATIGUE	Ibandronate_4_IVAndOral		4 (0.45, 36.64)	0.1	0.21 (-0.05, 0.71)	0.21	0.3 (-0.1, 0.7)
	FATIGUE	Risedronate_1_Oral		0.62 (0.09, 4.05)	0.1	-0.04 (-0.09, 0.21)	0.21	-0.07 (-0.18, 0.31)
	FATIGUE	Zoledronic_acid_1_IV	1.94 (1.32, 2.84)	1.9 (0.96, 3.94)	0.1	0.08 (0, 0.21)	0.21	0.12 (-0.01, 0.3)
	FATIGUE	Zoledronic_acid_2_IV	1.76 (1.14, 2.73)	2.38 (1.22, 5.15)	0.1	0.11 (0.02, 0.27)	0.21	0.18 (0.04, 0.37)
	FATIGUE	Zoledronic_acid_4_IV		2.43 (0.98, 6.75)	0.1	0.12 (0, 0.33)	0.21	0.18 (0, 0.43)
	FEBRILE NEUTROPENIA	Clodronate	1.77 (0.52, 6.04)	1.42 (0.27, 6.33)	0.0040	0 (0, 0.02)
	FEBRILE NEUTROPENIA	Ibandronate		4.65 (0.54, 39.94)	0.0040	0.02 (0, 0.14)
	FEBRILE NEUTROPENIA	Zoledronic_acid	0.27 (0.03, 2.51)	0.35 (0.04, 3.24)	0.0040	0 (0, 0.01)
	FEVER	Clodronate_1_Oral		6.54 (1.84, 45.74)	0.01	0.06 (0.01, 0.36)
	FEVER	Ibandronate_3_Oral		8.83 (2.48, 60.44)	0.01	0.09 (0.02, 0.42)
	FEVER	Zoledronic_acid_1_IV	17.55 (4.24, 72.7)	27.03 (10.19, 179.58)	0.01	0.25 (0.1, 0.69)
	FEVER	Zoledronic_acid_2_IV	34.76 (8.48, 142.55)	30.72 (11.84, 178.43)	0.01	0.27 (0.12, 0.68)
	FEVER	Zoledronic_acid_4_IV		6.8 (2.23, 38.99)	0.01	0.07 (0.02, 0.32)
	GGT increased	Clodronate_1_Oral	5.04 (0.24, 105.07)	5.86 (0.18, 164076396.26)	0.0003	0 (0, 1)
	HAND-FOOT SYNDROME	Clodronate_1_Oral	3.02 (0.12, 74.25)		0.0080
	HAND-FOOT SYNDROME	Zoledronic_acid_1_IV	0.91 (0.05, 17.05)		0.0080
	HAND-FOOT SYNDROME	Zoledronic_acid_2_IV	2.08 (0.12, 36.73)		0.0080
	HEADACHE	Clodronate_Oral		1.6 (0.47, 3.18)	0.24	0.1 (-0.11, 0.26)
	HEADACHE	Ibandronate_Oral		1.89 (0.64, 4.17)	0.24	0.13 (-0.07, 0.33)
	HEADACHE	Risedronate_Oral		1.11 (0.26, 4.09)	0.24	0.02 (-0.16, 0.32)
	HEADACHE	Zoledronic_acid_IV	2.19 (1.36, 3.52)	2.29 (1.32, 3.93)	0.24	0.18 (0.05, 0.31)
	HEPATOTOXICITY	Bisphosphonate	1.42 (0.98, 2.05)	1.31 (0.77, 2.06)	0.26	0.06 (-0.05, 0.16)
	HOT FLUSHES	Bisphosphonate	0.91 (0.71, 1.18)	0.88 (0.66, 1.18)	0.24	-0.02 (-0.07, 0.03)	0.32	-0.03 (-0.08, 0.04)
	HYPERGLYCAEMIA	Clodronate_1_Oral	0.62 (0.26, 1.49)		0.0100
	HYPERGLYCAEMIA	Zoledronic_acid_2_IV	2.55 (0.99, 6.61)		0.0100
	HYPERTENSION	Nitrogenous	0.84 (0.21, 3.28)	0.61 (0.15, 2.37)	0.02	-0.01 (-0.02, 0.02)	0.16	-0.06 (-0.13, 0.15)
	HYPERTENSION	Non_nitrogenous		0.82 (0.19, 3.29)	0.02	0 (-0.01, 0.04)	0.16	-0.02 (-0.12, 0.22)
	hypertonia/muscle spasms	Bisphosphonate	3.68 (1.12, 12.05)	3.57 (0.94, 22.24)	0.04	0.1 (0, 0.46)
	hypoalbuminemia	Bisphosphonate	5.04 (0.24, 105.07)	3.12 (0.13, 163.97)	0.0003	0 (0, 0.05)
	HYPOCALCEMIA	Bisphosphonate	1.6 (1.03, 2.51)	1.5 (0.76, 2.81)	0.04	0.02 (-0.01, 0.07)
	HYPOKALAEMIA	Nitrogenous	1.55 (0.4, 6.09)	1.48 (0.49, 4.38)	0.01	0.01 (-0.01, 0.04)
	HYPOKALAEMIA	Non_nitrogenous	2.36 (0.61, 9.12)	1.9 (0.63, 5.67)	0.01	0.01 (0, 0.05)
	hyponatremia	Nitrogenous		3.19 (0.3, 238.79)	0.0003	0 (0, 0.07)
	hyponatremia	Non_nitrogenous	7.06 (0.36, 136.81)	3.03 (0.3, 232.19)	0.0003	0 (0, 0.07)
	Hypophosphatemia	Clodronate_1_Oral	0.34 (0.01, 8.24)		0.0006
	increased bone pain	Bisphosphonate	1.84 (1.37, 2.48)	1.86 (1.15, 3.08)	0.11	0.08 (0.02, 0.17)
	INFECTION	Bisphosphonate	1.36 (0.93, 1.99)	1.04 (0.23, 3.51)	0.22	0.01 (-0.16, 0.28)	0.0009	0 (0, 0)
	Influenza-like symptoms	Bisphosphonate	7.36 (0.37, 147.29)	2.03 (0.09, 42.41)	0.03	0.03 (-0.03, 0.57)
	INR increased	Clodronate_1_Oral	0.09 (0.01, 1.65)		0.0030
	INSOMNIA	Clodronate_1_Oral		0.93 (0.35, 2.39)	0.05	0 (-0.03, 0.06)	0.08	-0.01 (-0.05, 0.1)
	INSOMNIA	Ibandronate_3_Oral		0.87 (0.32, 2.29)	0.05	-0.01 (-0.03, 0.05)	0.08	-0.01 (-0.06, 0.09)
	INSOMNIA	Risedronate_1_Oral		1.23 (0.03, 27.08)	0.05	0.01 (-0.05, 0.52)	0.08	0.02 (-0.08, 0.63)
	INSOMNIA	Zoledronic_acid_1_IV	1.83 (0.44, 7.58)	1.13 (0.46, 2.71)	0.05	0.01 (-0.02, 0.07)	0.08	0.01 (-0.04, 0.12)
	INSOMNIA	Zoledronic_acid_2_IV	1.12 (0.41, 3.05)	1.12 (0.47, 2.54)	0.05	0.01 (-0.02, 0.06)	0.08	0.01 (-0.04, 0.1)
	INSOMNIA	Zoledronic_acid_4_IV		0.74 (0.29, 1.8)	0.05	-0.01 (-0.03, 0.03)	0.08	-0.02 (-0.06, 0.06)
	IRREGULAR MENSTRUATION	Bisphosphonate	1.08 (0.5, 2.36)	0.92 (0.36, 2.19)	0.02	0 (-0.01, 0.03)
	ISCHAEMIC CARDIOVASCULAR DISEASE	Zoledronic_acid	5.91 (0.24, 145.97)	3.71 (0.09, 1180.23)	0.0030	0.01 (0, 0.8)
	ISCHAEMIC CEREBROVASCULAR EVENT	Bisphosphonate	2.41 (0.68, 8.54)	1.49 (0.4, 6.88)	0.0020	0 (0, 0.01)
	LEUCOCYTOPAENIA	Clodronate	1.11 (0.66, 1.9)	1.01 (0.43, 2.03)	0.7	0 (-0.2, 0.13)
	LEUCOCYTOPAENIA	Ibandronate		0.75 (0.21, 1.78)	0.7	-0.06 (-0.37, 0.11)
	LEUCOCYTOPAENIA	Risedronate		0.12 (0, 2.39)	0.7	-0.48 (-0.69, 0.15)
	LEUCOCYTOPAENIA	Zoledronic_acid		0.98 (0.24, 2.2)	0.7	0 (-0.34, 0.14)
	lipase increased	Clodronate_Oral	9.08 (0.49, 168.86)	12.14 (0.45, 798708.37)	0.0003	0 (0, 1)
	LIVER PROBLEMS	Zoledronic_acid_IV	0.15 (0.03, 0.83)	0.06 (0.01, 0.65)	0.08	-0.07 (-0.08, -0.03)
	LOSS OF APPETITE	Bisphosphonate	0.8 (0.22, 3)	0.46 (0.06, 2.41)	0.0030	0 (0, 0)
	LYMPHOEDEMA	Bisphosphonate	0.97 (0.13, 7.27)	0.7 (0.15, 3.99)	0.27	-0.06 (-0.22, 0.32)
	LYMPHOPAENIA	Bisphosphonate	0.49 (0.15, 1.66)	0.32 (0.06, 1.16)	0.01	-0.01 (-0.01, 0)
	MOTOR NEUROPATHY	Clodronate_1_Oral	0.67 (0.11, 4.02)		0.18
	MOTOR NEUROPATHY	Zoledronic_acid_2_IV	1.1 (0.68, 1.79)		0.18
	MUCOSITIS	Bisphosphonate	0.76 (0.26, 2.25)	0.46 (0.03, 1.73)	0.03	-0.01 (-0.03, 0.02)
	MUSCULOSKELETAL PAIN/EVENT	Bisphosphonate	1.2 (0.79, 1.82)	1.26 (0.71, 2.77)	0.11	0.03 (-0.03, 0.15)	0.0004	0 (0, 0)
	Nasopharyngitis	Zoledronic_acid_1_IV	0.48 (0.14, 1.72)		0.08
	Nasopharyngitis	Zoledronic_acid_2_IV	1.33 (0.28, 6.38)		0.08
	NAUSEA	Bisphosphonate	1.23 (0.87, 1.73)	1.31 (0.86, 2.14)	0.34	0.06 (-0.03, 0.18)	0.05	0.02 (-0.01, 0.06)
	neuralgia	Clodronate_Oral	4.03 (0.45, 36.14)	1.96 (0.03, 21.2)	0.02	0.02 (-0.02, 0.25)
	neuralgia	Zoledronic_acid_IV	0.15 (0.03, 0.83)	0.25 (0.02, 7.4)	0.02	-0.01 (-0.02, 0.1)
	NEUROSENSORY PROBLEMS	Bisphosphonate	1.56 (1.1, 2.21)	1.49 (1, 2.23)	0.1	0.04 (0, 0.1)	0.0000	0 (0, 0)
	NEUTROPENIA	Nitrogenous	2.04 (0.7, 5.93)	2.33 (1, 5.43)	0.04	0.05 (0, 0.15)
	NEUTROPENIA	Non_nitrogenous	0.68 (0.46, 1)	0.68 (0.36, 1.3)	0.04	-0.01 (-0.03, 0.01)
	neutrophil count decreased	Bisphosphonate	0.67 (0.49, 0.91)	0.62 (0.09, 1.18)	0.07	-0.02 (-0.06, 0.01)
	OEDEMA	Nitrogenous	1.3 (0.8, 2.1)	1.27 (0.8, 2)	0.11	0.03 (-0.02, 0.09)
	OEDEMA	Non_nitrogenous		1.09 (0.63, 1.85)	0.11	0.01 (-0.04, 0.07)
	oesophagitis	Clodronate	5.04 (0.24, 105.07)	1.11 (0.11, 7.43)	0.01	0 (-0.01, 0.07)
	oesophagitis	Ibandronate	2.46 (0.77, 7.9)	3.25 (0.77, 15.68)	0.01	0.03 (0, 0.15)
	oesophagitis	Zoledronic_acid	0.15 (0.03, 0.83)	0.19 (0.02, 1.4)	0.01	-0.01 (-0.01, 0)
	OsteoNecrosis of the Jaw	Zoledronic_acid_1_IV	11.71 (0.65, 212.64)		0.0050
	OTHER EYE DISORDERS	Clodronate_Oral		0.22 (0.03, 10.62)	0.03	-0.03 (-0.03, 0.24)	0.0000	0 (0, 0)
	OTHER EYE DISORDERS	Ibandronate_Oral		0.34 (0, 24.84)	0.03	-0.02 (-0.03, 0.44)	0.0000	0 (0, 0)
	OTHER EYE DISORDERS	Risedronate_Oral		0 (0, 0.32)	0.03	-0.03 (-0.03, -0.02)	0.0000	0 (0, 0)
	OTHER EYE DISORDERS	Zoledronic_acid_IV	1.12 (0.61, 2.06)	0.42 (0.1, 1.61)	0.03	-0.02 (-0.03, 0.02)	0.0000	0 (0, 0)
	pain in extremity	Bisphosphonate	2.29 (0.43, 12.16)	1.53 (0.42, 9.74)	0.14	0.06 (-0.08, 0.48)	0.05	0.03 (-0.03, 0.3)
	PANCREATITIS	Clodronate_Oral	5.05 (0.59, 43.24)	1.99 (0.26, 18.61)	0.0006	0 (0, 0.01)	0.0004	0 (0, 0.01)
	PANCREATITIS	Ibandronate_Oral		0 (0, 0.14)	0.0006	0 (0, 0)	0.0004	0 (0, 0)
	PANCREATITIS	Zoledronic_acid_IV		0.39 (0, 6.52)	0.0006	0 (0, 0)	0.0004	0 (0, 0)
	PARAESTHESIA	Zoledronic_acid_IV	1.02 (0.25, 4.1)	0.54 (0.14, 3.09)	0.43	-0.14 (-0.33, 0.27)
	PNEUMONIA	Bisphosphonate	1 (0.39, 2.54)	0.88 (0.2, 2.7)	0.0060	0 (0, 0.01)
	PULMONARY EMBOLUS	Zoledronic_acid_1_IV	2.69 (0.11, 67.11)		0.02
	renal impairment	Bisphosphonate	2 (0.63, 6.31)	1.36 (0.34, 4.92)	0.03	0.01 (-0.02, 0.11)	0.0004	0 (0, 0)
	SKIN DISORDER	Bisphosphonate	1.6 (1.03, 2.48)	1.48 (0.87, 2.44)	0.05	0.02 (-0.01, 0.06)
	STOMATITIS	Zoledronic_acid_1_IV	0.62 (0.13, 2.99)	0.39 (0.09, 2.8)	0.15	-0.09 (-0.14, 0.18)
	STOMATITIS	Zoledronic_acid_2_IV	0.23 (0.04, 1.2)	0.16 (0.03, 1.22)	0.15	-0.13 (-0.15, 0.03)
	SYNCOPE	Nitrogenous	3 (0.1, 90.96)	1.13 (0.11, 15.9)	0.0040	0 (0, 0.06)
	SYNCOPE	Non_nitrogenous	1.21 (0.37, 3.97)	0.78 (0.14, 3.31)	0.0040	0 (0, 0.01)
	THROMBOEMBOLIC EVENTS	Clodronate		16.15 (0.86, 206.82)	0.02	0.22 (0, 0.78)	0.0009	0.01 (0, 0.15)
	THROMBOEMBOLIC EVENTS	Ibandronate		33.15 (1.62, 474.44)	0.02	0.38 (0.01, 0.88)	0.0009	0.03 (0, 0.3)
	THROMBOEMBOLIC EVENTS	Zoledronic_acid	7.97 (1.4, 45.55)	4.38 (0.53, 46.06)	0.02	0.06 (-0.01, 0.46)	0.0009	0 (0, 0.04)
	THROMBOPAENIA	Zoledronic_acid_IV	0.29 (0.01, 7.28)	0.13 (0.01, 1.88)	0.04	-0.04 (-0.04, 0.04)
	THYROID CANCER	Zoledronic_acid	3 (0.1, 90.96)	0.04 (0, 2.19)	0.09	-0.09 (-0.09, 0.09)
	TRAUMATIC FRACTURES	Risedronate_1_Oral	NA (NA, NA)		0.0060
	uterine polyp	Bisphosphonate	3 (0.1, 90.96)	1.57 (0.04, 123.96)	0.09	0.05 (-0.09, 0.83)
	VAGINAL BLEEDING	Bisphosphonate	4.03 (0.45, 36.39)	3.24 (0.3, 339.48)	0.0020	0 (0, 0.4)
	VAGINAL DISCHARGE	Zoledronic_acid	0.43 (0.11, 1.72)	0.14 (0.03, 0.54)	0.06	-0.05 (-0.06, -0.03)
	VOMITING	Nitrogenous	4 (0.72, 22.09)		0.19		0.0004

Other things to include in the paper

• Simple meta-analysis

Should it be odds ratio, not risk difference, until we’ve discussed baseline? Discuss heterogeneity in ORs vs RDs To illustrate this, just point to forest plot ORs for homogeneity. Can we discuss het in baselines when choosing a baseline. Question whether we should be discussing risk differences here at all - as we want to make the baselines transparent. Could mention baseilne het as a motivator for picking a constant baseline. Just needs quick summary using direct-only data to motivate.

Group symptoms by class as in NMA results? Show number of studies contributing to the result in the row label

The data extracted from the 59 trials that fulfilled our criteria is shown in Supplementary Data 1. What is this?

Table 1 shows the study chars. Where is this? Should include blinding, follow up, any other data extracted

Subset analysis done for direct as well as NMA? [ suggest no! ]

• NMA

notAI - indicate in supp Table 1 - is this table in there?

Appendix plots in progress. Adding more transparent direct data and model comparison

• AZURE

both risk ratio and risk difference?

point out which are sig in azure alone

Methods

1. Talk through how we did FEVER

2. Forest plots for selected odds ratios

Healthy women analysis